Results of Two Open Label Multicenter Phase II
Pilot Studies (BCIRG 101 and 102) with
Trastuzumab (Herceptin®) in Combination with
Docetaxel and Platinum salts (Cis- or
Carboplatin) (TCH) as Therapy for Advanced
Breast Cancer in Women Over-Expressing the
HER2-neu Proto-Oncogene
J.-M. Nabholtz, T. Pienkowski, D. Northfelt,
W. Eiermann, E. Quan, P. Fumoleau, R. Patel, J. Crown,
D. Toppmeyer, L. Yonemoto, M.-A. Lindsay, C. Loret,
S. Blitz, M. Press, M. Pegram, A. Riva, D. Slamon
Breast Cancer International Resarch Group (BCIRG)
University of California Los Angeles, (UCLA)
Los Angeles, CA
Rationale/Introduction
•
•
In MBC:
•
Trastuzumab elicits objective clinical responses in patients with HER2+ MBC
•
Clinical outcomes are improved (including overall survival) with the addition of
trastuzumab to chemotherapies such as paclitaxel or anthracyclines
•
Cardiac toxicity may be limiting when Herceptin is used with anthracyclines
•
Docetaxel and platinum salts are active agents in first line MBC
In-Vivo and In-Vitro synergy findings
•
Platinum salts and docetaxel when combined with trastuzumab are extremely
synergistic
•
TCH is a novel regimen for incorporation into the adjuvant treatment of
HER2 positive, early breast cancer due to the documented synergy and
possibility of avoiding the cardiac toxicity of anthracyclines and
Herceptin
•
These studies piloted both platinum salts in TCH prior to utilization in
ongoing BCIRG phase III adjuvant and metastatic studies
Study Objectives
• Primary:
Safety
Response rate
• Secondary:
Duration of Response
Time to Progression
Survival
October 2001
ENROLLMENT CRITERIA
• Metastatic breast cancer
•
Amplification/Overexpression of HER2 (by immunohistochemistry
(Dako 2+ or 3+) or fluorescence in situ hybridization (FISH)
• (FISH status is retrospectively tested on all patients on primary tumor)
• Stage IIIB or IV
• Prior adjuvant or neo-adjuvant allowed
• Prior chemotherapy for MBC:
• TCarboH: One allowed
• TCisH: Not allowed
• Prior treatment with taxanes or platinum salts
• TCarboH: Monochemotherapy allowed
• TCisH: Not allowed
• Measurable disease (including lytic bone lesions by MRI)
• ECOG  2
• Normal baseline LVEF, and hepatic, renal, and bone marrow
function within acceptable range
Treatment Dosage
Taxotere
Platinum Salt
Herceptin
BCIRG 101
TCisH
BCIRG 102
TCarboH
75 mg/m2
75 mg/m2
Cisplatin
75 mg/m2
4mg/kg loading
2 mg/kg weekly
Carboplatin
6 AUC
4mg/kg loading
2 mg/kg weekly
October 2001
Schema of Administration
Taxotere
Platinum Salt
Every 3 weeks
At least 6 cycles
Herceptin weekly until PD
Premedication
•Standard Taxotere premed
•Standard CDDP hydration
October 2001
Patient and Tumor Characteristics
Number of centers
Number of Patients
Median Age (Range)
ECOG PS
Organs involved
Organ involvement
- Visceral
- Liver
- Lung
- Brain
Bone Metastases
Bone Lytic only
0
1
2
1-2
> 3 organs
BCIRG 101
TCisH
17
62
52 (29-76)
40 (65%)
20 (32%)
2 (3%)
40 (65%)
22 (35%)
43
24
25
1
29
4
(69%)
(39%)
(40%)
(2%)
(47%)
(6%)
BCIRG 102
TCarboH
21
62
54 (31-76)
36 (58%)
25 (40%)
1 (2%)
42 (68%)
20 (32%)
43 (70%)
16 (26%)
31 (51%)
3 (5%)
28 (46%)
5 (8%)
Prior Chemotherapy
Prior Adjuvant CT
Anthracycline CT
Prior Adjuvant Taxane
Prior MBC CT
BCIRG 101
TCisH
N=62
BCIRG 102
TCarboH
N=62
36 (58%)
35 (56%)
20 (32%)
28 (45%)
0
9 (15%)
0
3 (5%)
Treatment Administration (I)
BCIRG 101
TCisH
62
BCIRG 102
TCarboH
62
389
385
6 (3-8)
6 (2-13)
Herceptin infusions
1937
1956
On CT
1146
1176
18 (7-24)
18 (4-43)
791
780
13 (1-51)
20 (2-61)
N
Chemotherapy Cycles
Median (Range)
Median (range)
After CT
Median (range)
Treatment Administration (II)
N
3
4
5
6
>6
TCH Cycles
TCH Discontinuations
PD
Went to Surgery
AE
Pt Withdrawal
BCIRG 101
TCisH
62
BCIRG 102
TCarboH
62
2
3
4
34 (55%)
19 (31%)
9 (15%)
6
2
2
35 (56%)
16 (26%)
10 (16%)
2
3
3*
1
6
0
3**
1
*1 pt with CHF (onset cycle 4, off cycle 5), 2 pts with Gr. 3 neurosensory (cycle 5)
**1 pt with Gr. 3 Diarrhea and edema (cycle 2), 1 pt with cardiac tamponade (cytology positive), 1 pt with
pancytopenia and electrolyte imbalance
October 2001
Severe/Gr. 3-4 Hematological Toxicity
N
Febrile Neutropenia
Infection
Septic death
Anemia
Thrombocytopenia
BCIRG 101
TCisH
BCIRG 102
TCarboH
62
8 (13%)
2 (3%)
0
6 (9%)
0
62
10 (16%)
0
0
4 (6%)
7 (12%)
October 2001
Non-Hematological Toxicity (I)
N
Alopecia
Asthenia
BCIRG 101
TCisH
62
Overall
Gr 3 / 4
BCIRG 102
TCarboH
62
Overall
Gr 3 / 4
58 (94%)
58 (94%)
NA
11 (18%)
43 (69%)
50 (81%)
NA
11 (18%)
56
43
45
29
16
25
23
11 (18%)
7 (11%)
7 (11%)
2 (3%)
0
2 (3%)
1 (2%)
43
26
32
31
18
1
2
7 (11%)
5 (8%)
3 (5%)
2 (3%)
0
0
0
Gastrointestinal
Nausea
Vomiting
Diarrhea
Stomatitis
Constipation
Renal (creatinine)
Ototoxicity
(90%)
(69%)
(73%)
(47%)
(26%)
(40%)
(37%)
(69%)
(42%)
(52%)
(50%)
(29%)
(2%)
(3%)
Non-Hematological Toxicity (II)
BCIRG 101
TCisH
BCIRG 102
TCarboH
62
62
N
Neurologic
Sensory
Motor
Myalgia/arthralgia
Peripheral edema
Skin rash/erythema
Nail changes
Overall
Gr 3 / 4
Overall
37 (60%)
7 (11%)
18 (29%)
25 (40%)
17 (27%)
17 (27%)
2 (3%)
1 (2%)
0
1 (2%)
1 (2%)
0
26 (42%)
9 (15%)
14 (23%)
20 (32%)
18 (29%)
9 (15%)
Gr 3 / 4
1
3
1
1
0
(2%)
(5%)
(2%)
(2%)
0
Cardiac Toxicity Monitoring
• Clinical: every cycle
• LVEF (MUGA or ECHO) at:
•
•
•
•
baseline
every 12 weeks
completion of chemotherapy
during Herceptin therapy
at any suspected change (TCarboH)
or every 3 months in follow-up (TCisH)
• Cardiac toxicity was recorded by NCI Toxicity scale
and by LVEF monitoring.
Cardiac Toxicity
BCIRG 101
TCisH
62
1 2 3 4
BCIRG 102
TCarboH
62
1 2 3 4
Function
15 11
1
0
8
9
1
0
Dysrhythmia
2
0
0
0
0
1
0
N
NCI Cardiac Term
Grade
2
Absolute LVEF Decrease
 10 points and < LNL
 15 points and < LNL
 20 points
2
4
4
2
3
2
TCisH - Response Rate
First Line Patients*
All patients were centrally assessed by two independent radiologists
Overall
FISH
positive**
FISH
negative**
CR
3
2
1
PR
46
25
15
SD
12
8
2
PD
1
0
1
49/62 (79%)
27/35 (77%)
16/19 (84%)
[66-88]
[59-90]
[60-96]
ORR
95% CI
* All patients are first line
** 8 patients did not have tumor samples available for FISH testing (6 PR and 2 SD)
TCarboH - Response Rate
First Line Patients*
Overall
FISH
positive**
FISH
negative**
CR
8
7
1
PR
23
16
6
MR
4
2
1
SD
13
6
7
PD
7
5
2
31/55 (56%)
23/36 (64%)
7/17 (41%)
ORR
95% CI
NE
[40-69]
4
[46-79]
[19-67]
2
2
* 3 patients were treated in second line (1 NC and 2 PD, FISH positive)
** 2 patients did not have tumor samples available for FISH testing (1 PR and 1 MR)
TCisH – Time to Progression
First line Patients *
Proportion Progression Free
1.0
0.8
Patients
62
Median TTP (months)
9.9
95% CI
[8.3-13.1]
Events
33
Censored
• Still responding
• Further TX
29
22
7
0.6
0.4
95% CI
0.2
0.0
0
Number at Risk
62
Cumulative Events
0
2
4
6
8
10
12
14
T ime to Disease Progression (months)
62
57
43
31
21
15
0
2
13
21
27
27
16
18
20
3
0
0
0
32
33
33
33
October 2001
* All patients are first line
TCisH– Time to Progression
First Line Patients by FISH Result*
FISH +
FISH -
35
19
12.7
7.9
95% CI
[9.2-13.1]
[5.8-13.2]
Events
17
11
Censored
• Still responding
• Further Therapy
18
14
4
8
5
3
Patients
Proportion Progression Free
1.0
Median TTP (months)
0.8
0.6
0.4
0.2
FISH Positive
FISH Negative
0.0
0
Number at Risk
35
19
2
4
35
19
33
16
6
8
10
12
14
T ime to Disease Progression (months)
25
11
21
6
13
5
11
4
2
1
16
18
20
0
0
0
0
0
0
* All patients are first line, 8 patients did not have tumor samples available for FISH testing
October 2001
TCarboH – Time to Progression
First line Patients *
Patients
59
Proportion Progression Free
Median TTP (months)
12.0
95% CI
[7.4-16.3]
1.0
Events
31
0.8
Censored
• Still responding
• Further TX
• Lost to follow-up
28
17
9
2
0.6
0.4
95% CI
0.2
0.0
0
Number at Risk
59
Cumulative Events
0
2
4
6
8
10
12
14
T ime to Disease Progression (months)
56
49
40
27
21
17
2
7
10
19
22
23
* 3 patients were treated in second line
16
18
20
13
9
5
0
25
28
30
31
October 2001
TCarboH – Time to Progression
First Line Patients by FISH Result*
FISH +
FISH -
38
19
17.0
7.4
95% CI
[9.1-NE*]
[6.7-12.0]
Events
15
15
Censored
•Still responding
•Further Therapy
•Lost to Follow-up
23
15
8
0
4
1
1
2
Patients
Median TTP (mos)
Proportion Progression Free
1.0
0.8
NE* = Not Estimable
0.6
0.4
0.2
FISH Positive
FISH Negative
0.0
0
Number at Risk
38
19
2
4
37
17
32
15
6
8
10
12
14
T ime to Disease Progression (months)
26
13
19
8
15
6
12
5
10
3
16
18
20
8
1
4
1
0
0
* 3 patients were treated in second line, 2 patients did not have tumor samples available for FISH testing
October 2001
Conclusions
• TCisH and TCarboH in these two separate multicenter phase II
trials of HER2 positive MBC patients show the regimens to be:
•
Feasible (6 cycles in almost all patients, 3 pts discontinued due to
adverse events in each study)
•
Safe, without any enhancement of the expected toxicity of the individual
agents
•
Very active in a population of MBC with poor prognosis
• These pilot studies are the basis of phase III trials in the
Adjuvant (BCIRG 006) and Metastatic (BCIRG 007) settings in
patients with HER2 positive tumors by FISH
October 2001
BCIRG 006
Adjuvant Breast Cancer
Node Positive and High Risk Node Negative
4 x Docetaxel
4 x AC
60/600 mg/m2
100 mg/m2
ACT
HER2 +
ACTH
FISH
1 Year Trastuzumab
N=3150
6 x Docetaxel and Platinum salts
75 mg/m2
75 mg/m2 or AUC 6
TCH
1 Year Trastuzumab
October 2001
BCIRG 007
Metastatic Breast Cancer
First Line
TH Docetaxel 100 mg/m
2
HER2 +
Trastuzumab until progression
FISH
N=444
TCH Docetaxel 75 mg/m and Platinum salts 75 mg/m /AUC 6
2
2
Trastuzumab until progression
October 2001
Acknowledgements
BCIRG 101
TCisH
Study Chairman: JM Nabholtz
BCIRG 102
TCarboH
Study Chairman: D Slamon
BCIRG
UCLA Research Network
T Pienkowski – Poland
W Eiermann – Germany
P Fumoleau – France
J Crown – Ireland
M Smylie – Canada
P Klimo – Canada
M Martin – Spain
G von Minckwitz – Germany
C Prady – Canada
M Namer – France
S Verma – Canada
E Conejo – Spain
H Roche – France
SC Tang – Canada
S Spadafora – Canada
B Walley – Canada
L Yelle – Canada
S. Blitz, O. Denis, M.A. Lindsay, C. Loret,
J. Mortimer, N. Noel, J. Zobel
D Northfelt – Rancho Mirage, CA
R Patel – Bakersfield, CA
E Quan – Long Beach, CA
D Toppmeyer – New Brunswick, NJ
J Glaspy – UCLA, CA
M Pegram – UCLA, CA
E Ellis – Seattle, WA
S George – Rancho Mirage, CA
N Ku – Redondo Beach, CA
B Overmoyer – Cleveland, OH
J Rubin – Monterey, CA
J Sanchez – Las Vegas, NV
S Tannenbaum – Inland Valleys, CA
J Trey – Cleveland, OH
D Villa – Santa Maria, CA
R Ansari – South Bend, IN
J Barstis – Valencia, CA
A Black – Valencia, CA
D Berdeaux – Great Falls, MT
T Bradley – Monterey, CA
T Budd – Cleveland, OH
G Carabulea – Long Beach, CA
S Davidson – Northridge, CA
P Gold – Seattle, WA
F Kass – Santa Barbara, CA
M Milder – Seattle, WA
M Mukopadhyay – Bakersfield, CA
G Patel – Fullerton, CA
S Sanani – Northridge, CA
C Singerman – Northridge, CA
G Swanson – Monterey, CA
J Tate – Cleveland, OH
NS Tchekmedyian – Long Beach, CA
M Territo – UCLA, CA
D Vicario – Vista, CA
A Wax – Las Vegas, NV
D Weng – Cleveland, OH
T Woliver – Santa Barbara, CA
N. Ryba, L. Yonemoto, N. Chorn, L. Gordon, and L. Mariscal